Investigation of Drug-Drug Interactions Mediated by the Atp-Binding Cassette Drug Transporters Abcb1 and Abcg2

A major cause of death in cancer is due to metastatic cancer cells that are resistant to conventional therapy. Multidrug resistance (MDR) caused by the overexpression of ATP-Binding Cassette (ABC) drug transporters ABCB1 and/or ABCG2 is a major obstacle in clinical cancer chemotherapy. In addition, the function of ABCB1 and ABCG2 has significant impact on the oral bioavailability, distribution and penetration of most clinically active drugs. Collectively, these two transporters confer resistance to, and limit the use of most conventional anticancer agents, as well as many newly developed targeted drugs, hence hampers the overall effectiveness of chemotherapeutic agents. Currently, the two most important research areas in studying ABC transporter-associated MDR in cancer chemotherapy are (1) to determine the pharmacological impact of ABCB1 and ABCG2 on the efficacy of targeted chemotherapeutic drugs, such as protein kinase inhibitors that are being used to treat various types of cancer. In particular, this aspect is essential for new FDA-approved chemotherapeutic drugs and drugs that are still in clinical development that only have limited information on the overall pharmacokinetics and pharmacodynamics. (2) To identify, characterize and develop novel candidate inhibitors that can directly inhibit the function and/or protein expression level of ABCB1 and/or ABCG2, thus restore drug sensitivity and improve clinical outcome in ABC drug transporter-positive MDR cancers. We have previously developed a fluorescent cell-based high-throughput drug screening platform to identify a large number of candidate drug substrates and candidate inhibitors of ABCB1 and/or ABCG2. However, most of these candidates have not yet been thoroughly studied in subsequent experiments. Therefore, further biochemical and pharmacological characterizations, both in vitro and in vivo, are required to confirm the interactions, to determine the true pharmacological impact of ABCB1 and/or ABCG2 on these therapeutic drugs, and to evaluate alternative therapeutic strategies or drug combinations in order to improve the overall efficacy of substrate drugs. Finally, we intend to characterize and develop potential candidate inhibitors that will be suitable for further development into clinically active chemosensitizers.

Project ID:PC10507-0262
External Project ID:MOST105-2320-B182-018